Process for the preparation of grignard reagents

ABSTRACT

Homogeneous catalyst solvent systems for the preparation of Grignard reagents and the running of Grignard reactions are disclosed. These systems are superior to existing techniques for running Grignard reactions in that they significantly reduce or completely eliminate the induction periods which occur in most Grignard reagent ( RMgX; where R Alkyl or Aryl and X Cl,Br or I) preparations and make possible the use of alkyl chlorides in the Grignard preparations instead of the more expensive alkyl bromides or iodides. The catalyst solvent systems are formed by the addition of small percentages of reducing hydrides, for example, LiAlH4, NaAlH4, NaAlH2(OCH2CH2OCH3)2 or NaAlH (OCH2CH2OCH3)3, to the ether solvents, such as diethyl ether, tetrahydrofuran, dibutyl ether or 1,2 dimethoxyethane.

[ 1 Sept. 11, 1973 PROCESS FOR THE PREPARATION OF GRIGNARD REAGENTS [75] inventor: jaroslav Vit, New York, NY.

[73] Assignee: National Patent Development Corporation, New York, NY.

[22] Filed: June 11, 1971 [21] Appl. N0.: 152,365

Related US. Application Data [63] Continuation-impart of Ser. No. 874,711, Nov. 6,

1969, Pat. No. 3,629,288.

{52] US. Cl. 260/665 G, 252/188, 260/448 AD [51] lnt. Cl. C071 3/02, C07f 5/06 [58] Field of Search 260/665 G France Corbett, 1257-1258 Primary ExaminerDaniel E. Wyman Assistant ExaminerA. P. Demers Attorney-Alvin Guttag 57 ABSTRACT Homogeneous catalyst solvent systems for the preparation of Grignard reagents and the running of Grignard reactions are disclosed. These systems are superior to existing techniques for running Grignard reactions in that they significantly reduce or completely eliminate the induction periods which occur in most Grignard reagent [RMgX; where R=Alkyl or Aryl and X C1,Br or 1] preparations and make possible the use of alkyl chlorides in the Grignard preparations instead of the more expensive alkyl bromides or iodides. The catalyst solvent systems are formed by the addition of small percentages of reducing hydrides, for example, LiAl1-l,,, NaA11-l NaAll-l (OCH CH OCH5) or NaAlH (OCH CH OCH to the ether solvents, such as diethyl ether, tetrahydrofuran, dibutyl ether or 1,2 dimethoxyethane.

11 Claims, No Drawings PROCESS FOR THE PREPARATION OF GRIGNARD REAGENTS CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation-in-part of copending application Ser. no. 874,711; filed Nov. 6, 1969 now U.S. Pat. No. 3,629,288.

iBACKGROUND OF THE INvENTION 1. Field of the Invention The invention relates to the preparation of Grignard reagents and the use thereof in running Grignard reactions.

2. Prior Art The preparation of Grignard reagents from alkyl or aryl halides and magnesium turnings in an ether solvent is well known. It is also known that the preparation of these reagents is often quite difficult. The formation of these reagents is inhibited by the presence of water and alcohols in the ethers and halides and by impurities on the surface of the magnesium turnings. The standard techniques for initiation of Grignard reactions is the addition of small amounts of 1,, methyl iodide (or like compounds) or the addition of preformed Grignard reagent to the solvents containing a small percentage of the total halide to be reacted. One then visually follows the color loss, in the case of 1 or waits until'the reaction is spontaneously running in the cases of the alkyl iodides or the preformed Grignards before further halide is added.

These techniques suffer from severe disadvantages. They must be followed visually, in commercial scale operations this is particularly difficult, and the presence of small amounts of acidically active hydrogen containing compounds destroys the catalytic activity of the additives. It is often found that reagent buildup becomes a serious problem when the reactions do not start within the expected time. Often this buildup causes an uncontrollable exothermic reaction when it finally does start. It is therefore an object of this invention to overcome the problems due to the presence of water and alcohols in the solvents and reagents, the presence of impurities on the surface of the magnesium and the difficulties incurred in controlling the induction period and the subsequent exothermic reaction.

SUMMARY or THE iNvENrIoN M which is covered with a thin layer of magnesium oxide and also contains absorbed moisture.

It has now been found that both the purification of the ether and the activation of the magnesium can be effected using the same reagent. All the impurities in the ether and on the surface of the magnesium can be converted into inert materials by the addition of a small amount of one of the following complex hydrides:

NaAlH(OR) (l) or NaAl1-1 (OR), (11) wherein R is RO(CH,),,, RO(CH,),,O(CH,),,,, or

wherein R is a lower alkyl group having l-4 carbon atoms;

R" is a lower alkyl group having 1-4 carbon atoms;

n is 2,3 or 4; and

m is 2,3 or 4.

The above complex hydrides are members of a larger group of compounds disclosed in copending application Ser. no. 874,711 now U.S. Pat. No. 3,629,288 as being useful in the purification of aprotic solvents.

According to said application, aprotic solvents such as ethers, hydrocarbons, certain olefins and tertiary amines, are purified by being treated with a compound of the formula:

'" NaAiHtOR); or Namaxon wherein R is R'o(cH, R'O(CH2)8, or RO(CH;)4, in which R is i 0113-, cm. or A(CH,).,; 'n being 2, 3 or 4 and A being in which R" is CHsor CgH5i As stated in my earlier copending application, all of the above compounds are prepared according to the method disclosed in French Pat. No. 1,515,582 by similar methods with appropriately varied starting materials and the methods disclosed in my other copending applications, now U.S. Pat. No. 3,625,622 Ser. Nos. 594,971 now abandoned; 611,845; and 626,664 now U.S.Pat. No. 3,507,895.

The complex hydrides of the formula (I) and (11) are soluble in ethers. The reaction products of said hydrides with the impurities contained in ethers are also soluble. Therefore, ethers after treatment with said hydrides remain clear. Excess amounts of the complex hydrides (1) and (11) in ethers are stable toward oxygen and therefore no inert atmosphere is required in the use, storage or handling thereof.In contact with magnesium, the above complex hydrides react quickly and quantitatively with traces of chemically bonded moisture leaving the surface of the metal clean and active for Grignard reactions. During both operations purior R is fication of the solvent and activation of the magnesium surface hydrogen is evolved. Cessation of hydrogen evolution indicates that a sufficient amount of complex hydride (I) or (11) has been added and that the activation is complete; both operations can be carried out at once or they can be done sequentially. Thus, there are two possible ways to utilize this invention; and both have their advantages:

a. Using a previously prepared catalyst-solvent system. This is convenient for operations using fresh ether.

b. Using a concentrated ether or aromatic hydrocarbon solution of complex hydride (I) or (II) for drying the ether and activating the magnesium. This is convenient for multiple batch operations using recovered ether.

Both hydrides (I) and (II) are soluble in aromatic hydrocarbons and ethers. Solutions of up to 80 percent concentration can be prepared. Their handling is safe and easy. The inevitable initiation period in a subsequent Grignard synthesis in systems treated with hydrides (I) or (II) is significantly shortened and is always under control.

Other ether soluble hydrides such as LiAlI-I, and (i- C H AlH can also be used but they have the following disadvantages:

a. They are self inflammable and a protective, inert atmosphere is required in the storage and handling of the catalyst-solvent systems.

b. The reaction products of said hydrides with the impurities in the ether are insoluble and the ethers after being treated therewith, remain cloudy.

DESCRIPTION OF THE PREFERRED EMBODIMENT The catalyst solvent systems used in the invention can be prepared simply by mixing the ether soluble complex hydride with ether. The resulting solvent system must contain the hydride in an amount equivalent to from 0.005 to 0.1 gm. of active hydrogen per liter of ether. Total consumption of the hydride depends upon the total amount of impurities contained in the starting ether. Clear, oxygen stable solutions can only be obtained by using complex hydride (I) or (II). Therefore, low molecular weight complex hydride derivatives are most preferred. These are:

Sodium tris-(Z-methoxyethoxy) aluminum hydride; and

(Ill) NaAll-I (OCH CH OCH:,) Sodium bis(2-methoxyethoxy) aluminum hydride.

Both of these hydrides are viscous liquidsfrniscible with aromatic hydrocarbons. From the point of handling, the best form is a 70 percent solution thereof in benzene or toluene; traces of aromatic solvent in any ether will have no adverse influence on the Grignard reaction. Both of the complex hydrides (III) and (IV) differ in miscibility in ethers; NaAll-I(OCH CI-I OCI-I is completely miscible with all ethers while NaAlH (OCH,Cl-I OCH forms metastable solutions tending to separate in two immiscible liquid layers. The lower layer being of high concentration and very viscous. Furthermore, NaAlH,(OCI-I CH OCH forms etherates of low solubility with certain ethers (dioxane). Therefore, NaAlI-I (OCH,CH OCH has no limitations on its use, while the use of NaAll-I (OCH CI-l OCI-I is limited to tetrahydrofuran, glyme (CH OCH CH OCl-I diglyme (CH OCH CILOCH CH 0CH etc.

As mentioned above, there are two possible ways of utilizing this invention, i.e., using either the catalystsolvent system or a concentrate to initiate the Grignard reaction.

Each of these two ways will now be considered. Initiation By Catalyst-Solvent System Commercial anhydrous ether (diethyl ether) is charged into a vented vessel equipped with an agitator. The ventline is connected through a transparent liquidbubble seal filled with light mineral oil. The ether soluble complex hydride, preferably in the form of a concentrated solution, is then slowly added with agitation in small portions for as long as hydrogen gas is evolved. Hydrogen evolution is easy to follow in the bubble seal. Cessation of hydrogen evolution indicates complete active hydrogen (moisture and alcohols) and peroxide removal. An additional amount of the hydride is then added in order to reach the range of 0.005 to 0.1 g of active reducing hydrogen per liter of resulting catalystsolvent system. This solvent is then ready for use in any Grignard reaction. Magnesium turnings and catalystsolvent are charged into a conventional reactor equipped with a liquid bubble seal filled with light mineral oil. The mixture is then brought to the boiling point and refluxed as long as hydrogen is evolved (usually no longer than 5 minutes). After hydrogen evolution has stopped, the organic halide either neat or in solution can be added. The Grignard reaction starts with a much shorter induction period than is the case when using any other conventional procedure. The induction period for organic bromides and iodides is less than one minute. The less reactive organic chlorides have longer induction periods, usually not longer than 20 minutes. Initiation by Concentrate Magnesium turnings and ether are charged into a conventional reactor, vented through a liquid bubble seal and the mixture is brought to reflux. A soluble complex hydride, preferrably as a concentrated solution, is slowly added to the refluxing mixture in small portions until no further hydrogen is evolved. The addition of organic halide in the conventional manner can then begin. Results using both procedures are essentially the same. The time requirement using the concentrate is longer since the drying period of the solvent is longer (about 20 minutes) than the activation of the magnesium (less than 5 minutes).

EXAMPLES Preparation of the Catalyst-Solvent Example 1. 3 liters of diethylether (commercial anhydrous grade) were charged into a 5 liter round bottom flask with a dropping funnel, magnetic stirrer and bubble seal filled with light mineral oil, allowing free gas outlet and maintaining atmospheric pressure. The respective concentrated complex hydride solution was then added in the amount shown in Table l and the solvent was stirred until hydrogen evolution had stopped (l0-20 minutes). Samples of the resulting solvent were analyzed for reducing hydrogen content by iodometric titration.

Content of active ll in grams Solvent Hydride per itor Example:

21,. ((lzlImO NaAlH(OCHaCHzOCHs): 90 cc. of a 27% benzene solution 0.021 I .do LiAlH45 ee. 01' a 30% solution in THF 0.023 c ..d0 (i-CrHqhAlH-IOO cc. of a toluene solution 0. 039 ii. Tetrahydroiuran (THF) NaA1Hz(OCH2CHzOCH )z6O cc. of a 70% benzene solution. 0. 042 e 'lllF. NaAlHz(OCH2CHiOC4Hu)z75 cc. of a 50% toluene solution 0. 035 f C i'IgOCIIzCIhOCHs NaAlHz(OCH2CH2CH2CH2OCH3)260 cc. of a 50% glyme solution. 0.033 11- K N Z Z h a y flA 2l0CH2 H2N(CHa)z]z-50 cc. of a 70% benzene solution 0.031 h (0411010 NaAlH (0CH2CHzOCH3)3-13O cc. of a 70% benzene solution 0.027

Grignard Reagent Preparation Gridnard Synthesis Example 2. 5.3 grams (0.22 g-atom) of magnesium tumings and 130cc of the catalyst-solvent prepared as Example 3. The Grignard reagents RMgX was prein example l-were charged into a 500cc three-necked 5 pared as described in Example 2. Then, 0.2 mole of flask with mechanical stirrer, dropping funnel and recarbonyl compound was added in 100cc of ether and flux condenser vented through an oil filled bubble seal. the mixture refluxed for an additional 1 hour. The reac- The suspension was refluxed for five minutes and then tion mixture was cooled to room temperature and hy- 0.2 mole of organic halide diluted with an additional drolyzed with cc of water. Product identification and 70cc of the catalyst-solvent was added in portions. The 20 yield estimations were made by GLC analysis of the first portion of the halide about 10% of the whole volclear solution. The results are given in Table 3.

ume was added at once and the remainder dropwise TABLE 3. GRIGNARD SYNTHESIS Grignard reagent Carbonyl comp. Product Example:

a n-CtHpMgCl la CH3COC2H5 (DH CH3-(|:C2H5 87% I 04H); b CgH MgBl' 1a CBH5COCH3 0H CrHs-CCH3 78% I (RH; 0 i-CaHfMgCl 1C CaHmCHO CaHw-(FHOH iC3H7 after the induction period. At the end of theinduction M Example 4. The Grignard reagent RMgX was preperiod the solution usually turns cloudy and the reacpared as described in Example 2. Then 0.2 mole of cartion becomes exothermic. The reaction mixture was reboxyl compound in 10000 of ether was added. The refluxed until the reaction was completed and then anaaction mixture was refluxed for one additional hour, lyzed by halide ion titration. The results are as shown hydrolyzed and analyzed as described in Example 3. in Table 2. I The results are given in Table 4.

" W TABLE l-oltmNAnn SYNTHESIS (ll'ignard reagent Corboxyl comp. Product Example:

:1 1i--C4I-IqMgCl 1a olncoocnn nt CH3(|3C4H9 86% C-lHv b CrHsMgBr 1r C5H5COCl (0811930011 74% TABLE 2. Example 5. 5.3 grams (0.22 g-atom) of magnesium GRIGNARD REAGENT SYNTHESIS turmngs and 130cc of solvent (commercial anhydrous grade) were charged into the apparatus described in f Id Example 2. The mixture was brought to reflux and a so- Example 332 's g; 223 lution of complex hydride was added drop by drop until Table l) min. hr. hydrogen was no longer evolved. 0.2 mole of organic 45mm 2 Mm 90% halide in 70 cc of solvent was then added and the pro- 27 nC.H,Cl 1: 8mm Zhours 92% l 2 d n.QHBr 1a 1min u 4 cedure described In Examp e war 0 owe re r n v 91% were estimated by halide ion tltratlon. Theresults are T given in Table 5. e "3 l (Ila la 3 min lhour 90% f C.H Br la l min 1 hour 93% g t-C.H.-CH,Cl ld 20 min 3 hours 87% h C,H,,CH,CI 1f 15 min 2 hours 35% i n'C H CI lh 5 min 1 hour 88% j C,H,Br lb l min 56 hour 92% k i-C H Cl le 2 min 2 hours 90% l e lg l min A hour 89% m 2-C H NBr ll: 10 min 5 hours 84% TABLE 5.GRIGNARD REAGENT sfiq'rHEsrs Total reaction Organic time, Yield, halide Solvent Hydride hours percent Example:

:1 nClfinCl (CzHmO NaAlH(OCHzCHzOCHa)a-70% solution in benzene 3 87 I) i 00115131 TIIF NaAlHz(OCH2CHzOCH:)z70% solution in toluene 1% 8n 02115131 (CdImO LiAlH430% solution in THF 1% 90 What is claimed is: g

l. A method for preparing Grignard reagents comprising reacting an organic halide with magnesium metal in an ether solvent in the presence of a complex hydride of the formula:

NaAlH(OR) or NaAlH (OR) wherein R is a lower alkyl group, R" is a lower alkyl group, m is 2, 3 or 4, and n is 2, 3 or 4.

2. A method as claimed in claim 1 wherein the complex hydride is used in an amount corresponding to 0.005 to 0.1 gm of reducing hydrogen per liter of the ether solvent.

3. A method as claimed in claim 1 wherein the complex hydride is NaAll-l(OCl-[ Cl-i OCI-l or NaAlH- (OCH CH OCH 4. A method as claimed in claim 1 wherein the ether solvent is diethyl ether, dibutyl ether, tetrahydrofuran, glyme, diglyme or dioxane.

5. A method as claimed in claim 1 wherein the organic halide is an alkyl or aryl chloride, bromide or iodide.

6. A method as claimed in claim 1 comprising first preparing the ether solvent by adding the complex hydride to the ether, then adding the magnesium metal to the ether solvent and thereafter adding the organic halide to the ether solvent.

7. A method as claimed in claim 1 comprising first adding the magnesium metal to the ether solvent, then adding the complex hydride thereto and finally adding the organic halide to the ether solvent.

8. A method as claimed in claim 7 wherein the complex hydride is added in the form of a concentrated solution thereof in said ether or an aromatic hydrocarbon.

9. A method of activating magnesium metal for use in a Grignard reaction comprising adding magnesium metal to a composition consisting essentially of an ether solvent and a complex hydride of the formula glyme, diglyme or dioxane. 

2. A method as claimed in claim 1 wherein the complex hydride is used in an amount corresponding to 0.005 to 0.1 gm of reducing hydrogen per liter of the ether solvent.
 3. A method as claimed in claim 1 wherein the complex hydride is NaAlH(OCH2CH2OCH3)3 or NaAlH2(OCH2CH2OCH3)2.
 4. A method as claimed in claim 1 wherein the ether solvent is diethyl ether, dibutyl ether, tetrahydrofuran, glyme, diglyme or dioxane.
 5. A method as claimed in claim 1 wherein the organic halide is an alkyl or aryl chloride, bromide or iodide.
 6. A method as claimed in claim 1 comprising first preparing the ether solvent by adding the complex hydride to the ether, then adding the magnesium metal to the ether solvent and thereafter adding the organic halide to the ether solvent.
 7. A method as claimed in claim 1 comprising first adding the magnesium metal to the ether solvent, then adding the complex hydride thereto and finally adding the organic halide to the ether solvent.
 8. A method as claimed in claim 7 wherein the complex hydride is added in the form of a concentrated solution thereof in said ether or an aromatic hydrocarbon.
 9. A method of activating magnesium metal for use in a Grignard reaction comprising adding magnesium metal to a composition consisting essentially of an ether solvent and a complex hydride of the formula Na Al H(OR)3 or NA Al H2(OR)2 wherein R is R'' O (CH2)n, or R''O(CH2)n-O-(CH2)m-, or
 10. A method according to claim 9 wherein the complex hydride is Na Al H(OCH2CH2OCH3)2 or Na Al H2(OCH2CH2OCH3)2.
 11. A method according to claim 9 wherein the ether solvent is diethyl ether, dibutyl ether, tetrahydrofuran, glyme, diglyme or dioxane. 